The Cancer Testis Antigens (CTAs) are a group of germ cell proteins that are absent from normal somatic cells yet aberrantly expressed in many cancer cells. When mis-expressed in cancer cells, many CTAs promote tumorigenic characteristics including genome instability, DNA damage tolerance and therapy resistance. Here we highlight some of the CTAs for which their roles in genome maintenance in cancer cells are well established. We consider three broad CTA categories: (1) Melanoma Antigens (MAGEs) (2) Mitotic CTAs and (3) CTAs with roles in meiotic homologous recombination. Many cancer cells rely on CTAs to tolerate intrinsic and therapy-induced genotoxic stress. Therefore, CTAs represent molecular vulnerabilities of cancer cells and may provide opportunities for therapy. Owing to their high-level expression in tumors and absence from normal somatic cells, CTA-directed therapies could have a high level of specificity and would likely be devoid of side-effect toxicity.